We have identified a subset of CD4+ effector memory T cells (termed TEMRA cells) that are resistant to infection to CCR5-tropic (R5) HIV strains despite expressing high levels of cell surface CCR5. Remarkably, these cells are highly susceptible to HIV strains that enter cells via CXCR4 (X4-tropic). This peculiar subset is expanded in a portion of HIV-infected individuals and display relatively high CD4 cell numbers. The block to R5-tropic HIV infection in TEMRA cells is post-entry but prior to reverse transcription. These findings prompted us to better understand the mechanism of this unique intrinsic resistance mechanism in primary human T cells by pursuing the following aims: 1) Determine whether activation signals that can induce TEMRA-like cells from naive T cell subsets, which in turn become resistant to R5-tropic HIV infection. 2) Identify signals that can overcome the resistance of TEMRA cells. 3) Determine how TEMRA cells restrict HIV at the post-entry level. 4) Develop genetic screening approaches to identify potential intrinsic resistance factor(s) present in TEMRA cells. TEMRA cells serve as a tool for the identification of a novel means of host restriction. We believe the knowledge accrued from these studies is highly significant because identification of a novel intrinsic barrier to HIV infection can be: 1) Utilized to endow susceptible cells to be become resistant to infection;2) Used to amplify vaccine approaches by inducing HIV resistant T cells;and 3) Harnessed to develop novel therapeutic approaches that take advantage of intrinsic host resistance in primary T cells. Our focus on the identification of a novel barrier to HIV infection within primary CD4+ T cells is an additional strength of the proposed studies and will provide a framework for future applications. PUBLIC HEALTH RELEVANCE: We identified a subset of human T cells that resist HIV infection. In this application we aim to identify the mechanism that restricts HIV infection in this human T cell substance. The knowledge gained from the proposed studies would be highly significant because they can help identify mechanisms that endow resistance to T cells in HIV-infected individuals, both during infection and in designing therapeutic vaccines.